Colon cancer, which includes colorectal adenocarcinoma, primary or metastatic adenocarcinoma, and the like, is a major health concern today in terms of disease incidence. It has been estimated that one out of twenty-five Americans will develop some form of colon cancer during the course of his lifetime. Sugarbaker, P. H. et al., in Cancer, DeVita, V. T., et al. (Eds.), Lippincott Publ. Philadelphia, pp. 795-884 (1985).
In terms of treatment, surgery has been widely used with good, mixed or less than favorable results. Particularly among colon cancer patients with locally advanced or metastatic disease, the prognosis is extremely unfavorable with a high rate of morbidity and mortality.
Drug therapies have been tried with less than favorable results. The anti-neoplastic compound, 5-fluorouracil (5-FU), has been the major drug of choice in treating colon cancer, and its use has proven to be only marginally effective. 5-FU may reduce colon tumor size temporarily but there has been little evidence to show that the survival times of patients have been substantially prolonged or that "cures" are obtained (based on five year periods of remission). Chemotherapy with 5-FU has been used in patients with metastases to the liver, but temporary improvement is observed in only 25 percent or less of such cases, and the overall, survival is not significantly affected. LaMont, J. T. and Isselbacher, K. J., in Harrison's Principles of Internal Medicine (10th ed.) McGraw-Hill, New York, p. 1764, (1983). Despite the marginal effectiveness of 5-FU no other drugs or combination therapy has been convincingly shown to be more effective. Sugarbaker P. H. et al., supra. Woolley, P. V., et al., New Eng. J. Med., 312:1465 (1985).
Drug therapies have also been evaluated with respect to treating human cancer, e.g., human colon cancer xenograft lines, in which human tumors are serially heterotransplanted into immunodeficient, so called "nude" mice, and the mice then tested for their responsiveness to a specific drug. Giovanella, B. C., et al., Cancer 52(7):1146 (1983). The data obtained in these studies strongly support the validity of heterotransplanted human tumors, including colon tumors, into immunodeficient mammals, such as "nude" mice, as a predictive model for testing the effectiveness of anticancer agents.
The sodium salt of a naturally occurring alkaloid, camptothecin, was used in a brief clinical trial to evaluate toxic effects on patients with advanced incurable cancers. Gottlieb, G. A., et al., Cancer Chemotherapy Rep. 54:461 (1970). Few conclusions could be drawn from this study, although median survival for those patients responding to the treatment increased from about two months to about 3.5+ months.
Camptothecin derivatives or analogs have been synthesized and employed as antileukemic agents in mice (see e.g., Wani, M. C., et al., J. Med. Chem. 23:544, 1980; Wani, M. C., et al., J. Med. Chem. 30:1774 (1987); and Wani, M. C. et al., J. Med. Chem. 30:2317 (1987).
In U.S. Pat. Nos. 4,473,692 and 4,545,880, Miyasaka et al. disclose 10-substituted camptothecin derivatives and processes for their preparation. The 10-substituted camptothecin derivatives are said to possess anti-tumor activity with reduced or slight toxicity in comparison to the parent camptothecin compound. Miyasaka et al. do not disclose specific tumor targets nor do they indicate what level of reduced or slight toxicity is achieved by using their 10-substituted camptothecin compounds.
Recently, the enzyme, human topoisomerase I, has been examined in various human cancers, e.g., leukemia, lymphoma. Potmesil M. et al., Cancer Res. 48:3537 (1988). Human topoisomerase I is known to be a monomeric protein with an apparent molecular weight of 100,000 daltons. The swivel-like function of the enzyme has been implicated in various DNA transactions (replication, transcription and recombination). Purified mammalian topoisomerase I relaxes positively-supercoiled as well as negatively-supercoiled DNA in a mechanism which involves the transient breakage of one of the two DNA strands and the formation of a covalent topoisomerase I-DNA complex. In this complex, the enzyme is covalently linked to the 3'-phosphoryl end of the broken DNA backbone.
Recently, it was disclosed that topoisomerase I enzyme levels were on average higher in cancerous tissue, e.g., surgical specimens of colorectal carcinoma, in comparison to the enzyme level in normal mucosa (Hsiang, Y.-H., et al., Proc Ann Meet. of the Amer. Assoc. Cancer Res. 29:172 (1988) Abstract. Although it was stated that topoisomerase I could be considered as an alternative target in chemotherapy of this [colorectal carcinoma] disease, no disclosure or suggestion at all was made as to any specific topoisomerase I interacting drugs.
In view of very poor 5-year survival rates (approximately 50 percent or less) for patients undergoing conventional treatment for colonic cancer, e.g., surgical resection, or chemotherapy with 5-FU, it would be extremely useful to discover a new way to effectively treat human malignant colon tumors using drugs or compounds, following surgery, for example, which helps to establish the diagnosis and removes the bulk of cancer. The drug treatment would also be helpful for patients with advanced disease which has metastasized or spread to various organs, so that surgery is not feasible to remove all the cancerous tissues.